Acanthosis nigricans in a Chinese girl with FGFR3 K650 T mutation: a case report and literature review.

BACKGROUND: Acanthosis nigricans (AN) is a clinical manifestation featured by velvety brown plaques in skin folds that occurs in some hereditary and syndromic disorders. Fibroblast growth factor receptor 3 (FGFR3) mutations have been identified as one of the genetic causes of inherited AN. CASE PRESENTATION: A 17-year-old Chinese female had presented generalized acanthosis nigricans since she was 4 years old. She yielded no family history of short stature or AN. Apart from a short stature, no skeletal defects, neurological defects or other abnormalities were found. To identify the aetiology of the clinically diagnosed AN, we screened the proband for genetic mutations using whole exome sequencing. A heterozygous mutation (c.1949A > C, p.Lys650Thr) in FGFR3 was found in the proband. To date, 26 cases of AN harbouring this specific gene mutation have been reported in the literature, and only one child carried a de novo mutation instead of inheriting the specific mutation from their parents. The present case is the first-reported Chinese patient with isolated AN with a de novo K650 T mutation in FGFR3. CONCLUSIONS: We reported a new case of AN caused by a heterozygous mutation (c.1949A > C, p.K650 T) in FGFR3, and review the past reports of AN with the same gene mutation. Sequencing of the FGFR3 gene is a feasible approach to identify the aetiology of AN, especially for early onset extensive AN.

Mutational analysis of epidermal and hyperproliferative type I keratins in mild and moderate psoriasis vulgaris patients: a possible role in the pathogenesis of psoriasis along with disease severity.

BACKGROUND: Mutations in keratin proteins have been vastly associated with a wide array of genodermatoses; however, mutations of keratins in psoriasis have not been fully investigated. The main aim of the current research was to identify the mutation in K14, K10, K16, and K17 genes in two stages of psoriasis patients. METHODS: Ninety-six psoriatic skin biopsies were collected. mRNA transcript of K14, K10, K16, and K17 was prepared, amplified, and sequenced. Sanger sequences of all keratins were further validated for mutational analysis using Mutation Surveyor and Alamut Visual. Then, in silico analysis of protein stability and protein and gene expression of all keratins was performed and validated. RESULTS: Out of 44 mutations, about 75% of keratins are highly pathogenic and deleterious. Remaining 25% mutations are less pathogenic and tolerated in nature. In these 33 deleterious mutations were immensely found to decrease keratin protein stability. We also found a correlation between keratin and Psoriasis Area and Severity Index score which added that alteration in keratin gene in skin causes severity of psoriasis. CONCLUSIONS: We strongly concluded that acanthosis and abnormal terminal differentiation was mainly due to the mutation in epidermal keratins. In turn, disease severity and relapsing of psoriasis are mainly due to the mutation of hyperproliferative keratins. These novel keratin mutations in psoriatic epidermis might be one of the causative factors for psoriasis.

Síndrome metabólico y aterosclerosis carotídea subclínica en niños y adolescentes mexicanos con acantosis nigricans.

INTRODUCCIÓN: La acantosis nigricans es un marcador de resistencia a la insulina, la cual se asocia con alteraciones metabólicas y cardiovasculares. OBJETIVO: Investigar la frecuencia de síndrome metabólico y aterosclerosis carotídea subclínica en niños y adolescentes mexicanos con acantosis nigricans y comparar los resultados entre sexos. MÉTODO: Estudio transversal. Se incluyeron 30 sujetos masculinos y 30 femeninos con diagnóstico de acantosis nigricans, menores de 18 años. Se investigó síndrome metabólico (criterios de Cook), riesgo cardiovascular (proteína C reactiva ultrasensible [PCRus]) y aterosclerosis carotídea (grosor íntima-media). Para el análisis de datos se utilizó estadística descriptiva e inferencial. RESULTADOS: La frecuencia de síndrome metabólico fue de 43 % (sexo masculino 42 % versus femenino 58 %, p = 0.58). Todos presentaron niveles anormales de PCRus: 67 % fue clasificado con riesgo cardiovascular moderado y 27 % con riesgo alto. Frecuencia de aterosclerosis carotídea 98 % (masculino 49 % versus femenino 51 %, p = 0.45). La severidad de la acantosis nigricans no influyó en los resultados. CONCLUSIONES: La búsqueda intencionada de síndrome metabólico y aterosclerosis carotídea subclínica en niños y adolescentes mexicanos con acantosis nigricans, independientemente del sexo o severidad de la enfermedad, permitirá implementar medidas para disminuir la morbimortalidad en la edad adulta. INTRODUCTION: Acanthosis nigricans is a marker of insulin resistance that is associated with metabolic and cardiovascular alterations. OBJECTIVE: To investigate the frequency of metabolic syndrome and subclinical carotid atherosclerosis in children and adolescents with acanthosis nigricans, and to compare the results between genders. METHOD: Cross-sectional study, where 30 male and 30 female subjects younger than 18 years of age diagnosed with acanthosis nigricans were included. The presence of metabolic syndrome (Cook's criteria), cardiovascular risk (ultrasensitive C-reactive protein and [us-CRP]), and carotid atherosclerosis (intima-media thickness [IMT]) was investigated. Descriptive and inferential statistics was used for data analysis. RESULTS: The frequency of metabolic syndrome was 43% (males 42 % versus females 58%, p = 0.58). All patients showed us-CRP abnormal levels: 67% were classified with moderate cardiovascular risk and 27% with high risk. The prevalence of carotid atherosclerosis was 98% (males 49% versus females 51%, p = 0.45). Acanthosis nigricans severity did not influence on the results. CONCLUSIONS: Intentional search for metabolic syndrome and subclinical carotid atherosclerosis in Mexican children and adolescents with acanthosis nigricans, regardless of gender or disease severity, will enable the implementation of measures to decrease the morbidity and mortality seen in adult age.

Arterial stiffening, insulin resistance and acanthosis nigricans in a community sample of adolescents with obesity.

Acanthosis Nigricans (AN) is a common finding in adolescents with obesity. Little is known about its relevance for cardiovascular (CVS) risk, in particular arterial stiffening. We investigated associations between AN, conventional markers of CVS risk and carotid-radial pulse wave velocity (PWV) in a community sample of adolescents with obesity aged 12-19 recruited to an obesity trial. AN was present in 63% of subjects and 43% had severe grading. Presence of AN and severe AN were associated with z-score of body mass index (BMIz). Presence of AN (but not severity) was associated with abnormal or fasting hyperinsulinaemia but not after adjustment for BMIz. PWV data were available for 147 (84% of participants). Severe-grade AN was associated with PWV (co-efficient 0.51, 95% CI 0.13-0.89, P=0.01) but not when adjusted for BMIz, ethnic grouping and age. In our study presence and severity of AN offered little additional information on CVS risk beyond the degree of obesity itself. The relevance of AN for CVS risk should be interpreted with caution.

Correlation of Lipid Profile and Risk of Developing Type 2 Diabetes Mellitus in 10-14 Year Old Children.

BACKGROUND/AIMS: The role of lipid profile in predicting the risk of Type 2 diabetes mellitus (T2DM) in children is not clearly established. Our aim is to screen non-diabetic children aged 10-14 years for risk of developing T2DM and evaluate the association of abnormal lipids and socioeconomic status (SES). METHODS: Data on race/ethnicity, family history, body mass index percentile, blood pressure and presence of neck pigmentation (acanthosis nigricans) were collected from 149 non-diabetic children. Using these factors, children were classified into low risk (<3 risk factors) and high risk (>3 risk factors) groups. Logistic regression model and chi-square tests were used to evaluate the association of blood lipid profile and demographic variables. Independent t-test was used to compare the ratio of Total Cholesterol (TC) and High Density Lipids (HDL) with T2DM risk. RESULTS: 60% of children were at high risk for developing T2DM. HDL (p<0.001), triglycerides (p=0.02) and TC/HDL ratio (p<.001) were significantly abnormal in high risk group. Low SES showed a marginal association with high risk group. There were no gender or age differences between high and low risk groups. CONCLUSIONS: The significant determinants associated with high risk group were modifiable factors providing an opportunity for early intervention and prevention.

Breaking the silence: addressing skin issues in obese and overweight children.

Skin irritation and breakdown can cause considerable physical and psychological pain, yet skin alterations and hygiene issues are often not addressed during routine healthcare visits for children who are overweight and obese. The number of children with obesity has increased significantly, yet there is limited literature to assist children with the private physical symptoms and inconveniences that accompany obesity. Healthcare professionals focus on nutritional intake and activity and treat comorbidities related to obesity, since comorbidities affect quality of life, but so can the pain and embarrassment of skin issues. This article addresses skin issues related to being overweight and obese.

Does insulin resistance co-exist with glucocorticoid resistance in the metabolic syndrome? Studies comparing skin sensitivity to glucocorticoids in individuals with and without acanthosis nigricans.

BACKGROUND: The metabolic syndrome is associated with increased risk for both diabetes and coronary artery disease, which insulin resistance alone does not satisfactorily explain. We propose an additional and complementary underlying mechanism of glucocorticoid resistance. RESULTS: Using acanthosis nigricans (AN) and skin vasoconstrictor (SVC) response to topically applied beclomethasone dipropionate as markers of insulin and glucocorticoid resistance, respectively, we compared anthropometric, biochemical, pro-inflammatory markers and the SVC response in subjects with AN in two studies: STUDY 1 was used to compare subjects with AN (Grade 4, n = 32), with those without AN (n = 68) while STUDY 2 compared these responses among a cross-section of diabetic patients (n = 109) with varying grades of AN (grade 0, n = 30; grade 1, n = 24; grade 2, n = 18; grade 3, n = 25; grade 4, n = 12). FINDINGS: In both studies there was an inverse relationship between AN Grade 4 and the SVC response, (P < 0.001). In STUDY 1, AN Grade 4 was associated with age, waist circumference, BMI, fasting blood glucose, plasma lipids and hs-CRP (P < 0.05). SVC was an independent predictor of CRP and those with combined AN and a negative SVC response, CRP levels were highest. In Study 2 when the SVC response in subjects with type 2 diabetes mellitus with varying degrees of AN was studied, it showed that for any degree of AN, the SVC response is more likely to be negative and was independent of gender and ethnicity. CONCLUSION: An absent SVC response represents a new biomarker for the metabolic syndrome and the exaggerated inflammatory response, which characterizes the metabolic syndrome, may be an outcome of deficient glucocorticoid action in vascular tissue.

The role of metabolic syndrome components and adipokines in insulin resistance in prepubertal children.

OBJECTIVE: Insulin resistance has a central role in the pathophysiology of cardiovascular atherosclerotic disease. Adipose tissue is of capital importance in view of its production of adipokines. The present study aims to determine the association of metabolic syndrome components, which constitute risk factors for cardiovascular atherosclerotic disease, and leptin and adiponectin with insulin resistance in prepubertal children. METHODS: We conducted a cross-sectional study involving 197 children. Of these, 112 children were obese, 36 were overweight and 49 had normal weight. The association of sex, waist circumference, Acanthosis nigricans, age, BMI Z-score, serum lipids, leptin and adipocytokines with insulin resistance [defined as the homeostatic model assessment for insulin resistance (HOMA-IR) index higher than or equal to 2.5] was investigated using logistic regression. RESULTS: There was positive association of sex (female), age, BMI Z-score, triglycerides and leptin with insulin resistance (p<0.05). CONCLUSION: Among the conventional components of metabolic syndrome, the role of BMI Z-score and triglycerides stands out in insulin resistance of prepubertal children. Sex (female), age and leptin also showed to be of major importance.

Acanthosis nigricans: a warning sign of lower urinary tract dysfunction in obese children?

OBJECTIVE: There have been very few studies on the relationship between lower urinary tract dysfunction (LUTD) and obesity-related metabolic disorders in the pediatric age group. This study investigated the relationship between LUTD and metabolic disturbances in obese children. PATIENTS AND METHODS: Four-hundred obese children (body mass index ≥ 95th percentile) were included in the present study. Anthropometric, clinical, and biochemical parameters were evaluated. The Dysfunctional Voiding and Incontinence Scoring System (DVISS) questionnaire was administered and scores over 8.5 were considered to be reflective of LUTD. Subjects were stratified into two groups based on DVISS symptom scores - obese children with and without LUTD. The homeostasis assessment model was used to evaluate insulin resistance and the International Diabetes Federation criteria to identify metabolic syndrome. RESULTS: Lower urinary tract dysfunction was detected in 19% of the study population. There were no significant differences between the two groups in terms of laboratory results. No statistically significant relationship was found between LUTD and the presence of metabolic syndrome or insulin resistance; however, a significant association was observed between LUTD and acanthosis nigricans. Regression analysis revealed that only the presence of acanthosis nigricans significantly increased the risk of lower urinary tract dysfunction by 1.75-fold (p < 0.05). CONCLUSIONS: The presence of acanthosis nigricans in obese children may suggest the concurrent occurrence of lower urinary tract dysfunction and should be investigated accordingly.

Acanthosis nigricans as a composite marker of cardiometabolic risk and its complex association with obesity and insulin resistance in Mexican American children.

AIM: Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs). METHODS: We used data from 670 non-diabetic MA children, aged 6-17 years (49% girls). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes. RESULTS: Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q. CONCLUSION: Our study suggests that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children.

Falling short: When testing is mandated and follow-up is not.

In 1999, the Texas Legislature mandated acanthosis nigricans (AN) screening in primary schools in designated regions of the state through the passage of House Bill 1860 to identify children at risk for diabetes by identifying the skin condition AN. AN is related to insulin resistance, and, thus, is associated with type 2 diabetes (diabetes mellitus type 2 [DMT2]), a growing concern among school-aged children. Since 1999, millions of children have been screened and hundreds of thousands have been screened positive. No data are available about the effectiveness of the program in identifying DMT2 among the school-aged population because no follow-up is mandated. The current practice is to send a letter to the parents of the child who screens positive, advising the parents to take the child to a health care provider for further assessment. Hence, children within the state may have diabetes or are developing diabetes but have yet to be diagnosed. In light of the presence of a law mandating AN screening, mandating a follow-up to identify those who have diabetes or are developing the condition of diabetes can provide early intervention and decrease costs of care. It is not known why the follow-up of those who screen positive was not included in the initial legislation. It may have been due to the cost of the necessary blood tests that are used to assess an individual for diabetes. Related to this is the reality that blood tests are invasive procedures, whereas screening for a skin disorder is not, thereby possibly explaining the omission of mandated follow-up from the legislation .

Antibodies to purified insulin receptor have insulin-like activity.

Antibodies to insulin receptors purified from rat liver membranes do not complete with [125I]insulin for binding to the insulin receptor but do precipitate solubilized receptors labeled with [125I]insulin. These antibodies have the insulin-like activities of enhancing glucose oxidation and inhibiting epinephrine-induced lipolysis in rat adipocytes. Thus, antibody binds to the receptor at a different site from that to which insulin binds, yet the interaction can initiate an effective biological response. These results indicate that the previously studied insulin-binding sites are the physiological macromolecular receptors for insulin.

Obesity and the skin: skin physiology and skin manifestations of obesity.

UNLABELLED: Obesity is widely recognized as an epidemic in the Western world; however, the impact of obesity on the skin has received minimal attention. The purpose of this article is to highlight the association between obesity and dermatologic conditions. We review the impact of obesity on the skin, including skin physiology, skin manifestations of obesity, and dermatologic diseases aggravated by obesity. Obesity is responsible for changes in skin barrier function, sebaceous glands and sebum production, sweat glands, lymphatics, collagen structure and function, wound healing, microcirculation and macrocirculation, and subcutaneous fat. Moreover, obesity is implicated in a wide spectrum of dermatologic diseases, including acanthosis nigricans, acrochordons, keratosis pilaris, hyperandrogenism and hirsutism, striae distensae, adiposis dolorosa, and fat redistribution, lymphedema, chronic venous insufficiency, plantar hyperkeratosis, cellulitis, skin infections, hidradenitis suppurativa, psoriasis, insulin resistance syndrome, and tophaceous gout. We review the clinical features, evidence for association with obesity, and management of these various dermatoses and highlight the profound impact of obesity in clinical dermatology. LEARNING OBJECTIVE: After completing this learning activity, participants should be aware of obesity-associated changes in skin physiology, skin manifestations of obesity, and dermatologic diseases aggravated by obesity, and be able to formulate a pathophysiology-based treatment strategy for obesity-associated dermatoses.

Pigmented and thickened axillary folds.

Andrew, 45 years of age, presents with a 12 month history of dark, thickened skin in both axillae. He is concerned about the appearance and would like to know how to treat it. He is moderately obese, with a body mass index (BMI)of 31.2 kg (BMI = weight [kg] + height(2) [m(2)]) but is otherwise well and on no medication. There is no family history of any similar skin disorder.

Obesidad y piel / Obesity and skin

Introduction: Obesity is a growing global health problem; it may even be one of the worst public health issues. In Chile, 34.4% of the population is obese, therefore, is it important for clinicians to be aware of all the consequences of obesity. In this review, we will address the relation of four main dermatologic conditions with obesity: psoriasis, hidradenitis suppurativa, acanthosis nigricans and malignant melanoma. Material and methods: Search in pubmed for obesity and psoriasis, hidradenitis suppurativa, acanthosis nigricans and malignant melanoma. Results: Obesity has a direct impact in the prevalence and severity of psoriasis, hidradenitis suppurativa, acanthosis nigricans. The reduction on body weight has proven to reduce severity of psoriasis and hidradenitis suppurativa. Obese patients with psoriasis have a higher risk on adverse effects due to medication and less effectiveness of biological medications. Acanthosis nigricans is a clinical indicator of insulin resistance and a risk predictor for those with greater risk to develop diabetes in the future. The relationship between obesity and malignant melanoma is not clear and needs further research. Conclusion: Obesity is increasing, dermatologist will face this condition more frequently, it has a great impact over psoriasis, hidradenitis suppurativa, acanthosis nigricans and malignant melanoma, thus it should be considered in treatment decisions. (AU)

Evaluating health risk using a continuous metabolic syndrome score in obese children.

BACKGROUND: The metabolic syndrome (MS) in pediatrics is controversial. Rather than a dichotomous scale, a continuous metabolic syndrome score (cMets) has been proposed to evaluate MS. The aim of this study was to evaluate the utility of a cMets score among an ethnically diverse cohort of children with acanthosis nigricans (AN). METHODS: A retrospective chart review was used to extract clinical and laboratory information on a cohort of obese children. Criteria for MS components and the cMets score were established using published guidelines. Multiple linear regression evaluated the effect of AN status on MS and cMets. Fisher's exact test compared the race differential on the presence or absence of MS component disorders. RESULTS: MS diagnosis was non-significant when considering AN status (p=0.554) and ethnicity (p=0.431). Evaluation of the frequency of component disorders, revealed that Caucasians had significantly higher levels of abnormal triglycerides (TG) (35.1 vs. 10.3%; p<0.001), whereas African Americans had significantly higher homeostatic model assessment of insulin resistance (HOMA-IR) scores (51.3% vs. 22.3%; p<0.001). cMets was sensitive to identifying metabolic risk among Caucasians with AN, only (p=0.029). CONCLUSIONS: This study found differences in health risk among an obese, ethnically diverse sample of children. cMets is a more sensitive marker of metabolic change compared with MS, especially when AN status and race are considered. cMets may pose an opportunity for the clinician to evaluate the interaction of health risks on the health status of obese children.

Use of in vitro clonogenic assays to differentiate acquired from genetic causes of insulin resistance.

Insulin resistance may be due directly to genetically programmed disorders of insulin action or acquired defects in which environmental factors influence insulin action. To address the issue of this distinction, we studied the ability of insulin to stimulate colony formation in primary cultures of erythroid progenitors (assumed to retain environmental influences) and immortalized T lymphocytes (presumed to reflect only genetic influences). Four patients with hyperinsulinemia and disturbed glucose metabolism were studied (2 patients with acanthosis nigricans, 1 of whom had circulating anti-insulin-receptor antibodies, 1 with partial lipodystrophy, and 1 with Cushing's syndrome). The mean colony-forming ability of their erythroid progenitor cells in response to insulin stimulation (less than or equal to 1.6 pM) was significantly blunted compared with control cells (P less than 0.05). The mean responsiveness of their immortalized T-lymphoblast cell lines to similar insulin concentrations was no different than that of control T-lymphocyte lines, consistent with an acquired cause for the observed insulin resistance in each case. A T-lymphocyte line from a patient with leprechaunism, however, showed no stimulation in response to physiological concentrations of insulin. With these same in vitro methodologies, there was normal T-lymphocyte line responsiveness to insulinlike growth factor I (IGF-I) or insulin concentrations greater than 8.6 pM; both of these responses could be completely blocked by preincubation with an antibody to the IGF-I receptor. These findings suggest that, despite resistance to physiological levels of insulin, the high circulating insulin concentrations present in the serum of these patients could mediate unwanted tissue-specific growth through an intact IGF-I receptor-effector mechanism.

Can waist circumference identify children with the metabolic syndrome?

OBJECTIVE: To determine in children the association between waist circumference (WC) and insulin resistance determined by homeostasis modeling (HOMA-IR) and proinsulinemia and components of the metabolic syndrome, including lipid profile and blood pressure (BP). METHODS: Eighty-four students (40 boys) aged 6 to 13 years and matched for sex and age underwent anthropometric measurements; 40 were obese; 28, overweight; and 16, nonobese. Body mass index (BMI), WC, BP, and Tanner stage were determined. An oral glucose tolerance test, lipid profile, and insulin and proinsulin assays were performed. Children were classified as nonobese (BMI < 85th percentile), overweight (BMI, 85th-94th percentile), and obese (BMI > or = 95th percentile). RESULTS: There was univariate association (P < .01) between WC and height (r = 0.73), BMI (r = 0.96), Tanner stage (r = 0.67), age (r = 0.56), systolic BP (r = 0.64), diastolic BP (r = 0.61), high-density lipoprotein cholesterol level (r = 0.45), triglyceride level (r = 0.28), proinsulin level (r = 0.59), and HOMA-IR (r = 0.59). Multiple linear regression analysis using HOMA-IR as the dependent variable showed that WC (beta coefficient = 0.050 [95% confidence interval, 0.028 to 0.073]; P = .001) and systolic BP (beta coefficient = 0.033 [95% confidence interval, 0.004 to 0.062]; P = .004) were significant independent predictors for insulin resistance adjusted for diastolic BP, height, BMI, acanthosis nigricans, and high-density lipoprotein cholesterol level. CONCLUSION: Waist circumference is a predictor of insulin resistance syndrome in children and adolescents and could be included in clinical practice as a simple tool to help identify children at risk.

Acanthosis nigricans.

Acanthosis nigricans is thickened, velvety, hyperpigmented skin associated with a variety of endocrine disorders, malignancies and medications.